A series of Ce/Zr mixed-metal-organic frameworks with different topology/connectivity, namely, Ce/Zr-UiO-66 (U01, U02, and U03) (fcu (12-c)), Ce/Zr-DUT-67-PZDC (D01 and D02) (reo (8-c)), and Ce/Zr-MOF-808 (M01, M02, and M03) (spn (6-c)) were evaluated toward the detoxification of toxic nerve agent model diisopropylfluorophosphate (DIFP) at room temperature in unbuffered aqueous solution. Noteworthily, the catalytic rate for P-F bond cleavage increased with increasing Ce/Zr molar ratio. A further increase in catalytic activity can be achieved by Mg(OMe)2 doping of the mixed-metal MOFs as exemplified with M01@Mg(OMe)2 and M02@Mg(OMe)2 systems. The results show that Mg(OMe)2 incorporation into the mesoporous cavities of M01 and M02 give rise to P-F hydrolytic degradation half-lives of nearly 5 and 2 min with 100% degradation of DIFP after 55 and 65 min for M01@Mg(OMe)2 1:2 and M02@Mg(OMe)2 1:4, respectively.